Regulatory Effects of Ribosomal S6 Kinase 1 (RSK1) in IFNλ Signaling

Sonali Joshi,Barbara Kroczynska,Eleanor N Fish,Sergei V Kotenko,Leonidas C Platanias,Amit Verma,Elizabeth A Eklund

doi:10.1074/jbc.m110.183566

Abstract

Although the mechanisms of generation of signals that control transcriptional activation of Type III IFN (IFNλ)-regulated genes have been identified, very little is known about the mechanisms by which the IFNλ receptor generates signals for mRNA translation of IFNλ-activated genes. We provide evidence that IFNλ activates the p90 ribosomal protein S6 kinase 1 (RSK1) and its downstream effector, initiation factor eIF4B. Prior to its engagement by the IFNλ receptor, the non-active form of RSK1 is present in a complex with the translational repressor 4E-BP1 in IFNλ-sensitive cells. IFNλ-inducible phosphorylation/activation of RSK1 results in its dissociation from 4E-BP1 at the same time that 4E-BP1 dissociates from eIF4E to allow formation of eIF4F and initiation of cap-dependent translation. Our studies demonstrate that such IFNλ-dependent engagement of RSK1 is essential for up-regulation of p21(WAF1/CIP1) expression, suggesting a mechanism for generation of growth-inhibitory responses. Altogether, our data provide evidence for a critical role for the activated RSK1 in IFNλ signaling.

Highlights

The mechanisms of generation of signals that control transcriptional activation of Type III IFN (IFN␭)-regulated genes have been identified, very little is known about the mechanisms by which the IFN␭ receptor generates signals for mRNA translation of IFN␭-activated genes
We examined whether IFN␭ treatment of sensitive cell lines induces activation of the MEK/extracellular signal-regulated kinase (ERK) pathway and whether ribosomal protein S6 kinase 1 (RSK1) is activated by the Type III IFN receptor downstream of ERK
HT-29 cells were incubated for different times in the presence or absence of IFN␭, and cell lysates were resolved by SDS-PAGE and immunoblotted with antibodies against the phosphorylated forms of RSK1 and ERK1/2

Summary

Introduction

The mechanisms of generation of signals that control transcriptional activation of Type III IFN (IFN␭)-regulated genes have been identified, very little is known about the mechanisms by which the IFN␭ receptor generates signals for mRNA translation of IFN␭-activated genes. Despite engaging entirely different receptor complexes, Type I (␣, ␤, ␻) and Type III (␭) IFNs share common Jak-Stat pathways to mediate signals for transcription of target genes Both Type I IFNs and IFN␭ activate receptor-interacting tyrosine kinases Jak and Tyk, which in turn regulate phosphorylation of members of the STAT family [6, 7], leading to formation/assembly of the ISGF3 complex that regulates transcription via binding to interferon-stimu-. Despite the advances in the field and the emerging understanding of the mechanisms of Type III IFN-induced transcriptional activation, very little is known about the signals by which the Type III IFN receptor controls mRNA translation of target genes to induce IFN␭-dependent biological responses. Hormones, and mitogens control translation at that level by inducing activation of the mTOR kinase and mTOR-mediated 4E-BP1-phosphorylation, resulting in deactivation of 4E-BP1 and its dissociation from eIF4E [19, 24]

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Results

Conclusion